Tuberin is a product of the TSC2 tumor suppressor gene and an important regulator of cell proliferation and tumor development. Mutations in either TSC2 or the related TSC1 (hamartin) gene cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by development of multiple, widespread non-malignant tumors. Tuberin is directly phosphorylated at Thr1462 by Akt/PKB. Phosphorylation at Thr1462 and Tyr1571 regulates tuberin-hamartin complexes and tuberin activity. In addition, tuberin inhibits the mammalian target of rapamycin (mTOR), which promotes inhibition of p70 S6 kinase, activation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translation initiation), and eventual inhibition of translation. Tuberin is phosphorylated on Ser939 and Thr1462 in response to PI3K activation and that the human TSC complex is a direct biochemical target of the PI3K/Akt pathway. This data complements Drosophila genetics studies suggesting the possible involvement of the tuberin-hamartin complex in the PI3K/Akt mediated insulin pathway.